We propose to investigate specific and whole-genome level human genetic polymorphisms associated with severe leptospirosis infection. Leptospirosis is a disease of major importance throughout tropical and sub-tropical regions. Its polarized (<5% severe/fatal vs. usually non-severe) clinical features make it an ideal model for phenotype-genotype comparisons. While most patients with leptospirosis recover uneventfully, a minority develop hepatic, renal, and hemorrhagic manifestations, and some die despite intensive care and specific antimicrobial therapy. A rodent model of leptospirosis demonstrates that hypofunctional TLR4 predisposes to severe disease, but confirmation of this finding and exploration of genome-wide associations will be important in humans in whom multifactorial genetic susceptibility are most likely. The candidate is a pediatric infectious disease physician and former Centers for Disease Control and Prevention Epidemic Intelligence Service Officer with substantial field expertise in tropical infectious diseases seeking to acquire career skills focused on genetic susceptibility to severe infectious disease outcomes. He will greatly benefit from dual mentorship provided by Dr. Joseph Vinetz, physician-scientist and K24/R01-supported tropical medicine investigator, and Dr. Nicholas Schork, statistical genetics expert and recent co-recipient of an NIH Clinical Translational Science Award at the Scripps Translational Research Unit/former Co-Director of the UCSD Center for Human Genetics and Genomics. The candidate will take advantage of advanced clinical research programs at UCSD including the GCRC, the Genomics Center, and the Genetic Polymorphism Laboratory which function within ongoing NIH-funded training grants and international research projects. We seek a) to compare TLR2 and TLR4 (and adaptor protein) genotypes among severely and mildly infected leptospirosis patients and b) to determine genome-wide associations with leptospirosis outcome using high-density single nucleotide polymorphism microarray and haplotype analysis to characterize genomic variation associated with severe disease. Both of these approaches are promising leads toward further translational research and improved diagnostic, therapeutic, and preventive strategies. RELEVANCE: This project will provide a means to investigate mechanisms of leptospirosis pathogenesis and will serve as a superb research training mechanism based on the hypothesis that severe infectious disease susceptibility is attributable to specific defects in innate immune detection and signaling and also due to currently uncharacterized genomic variation.